The Modulation of Drug Efficacy and Toxicity by the Gut Microbiome

Molecular and Integrative Toxicology

Volumn , Issue , 2015, Pages 323-341

  Wilson, Ian D ^a   Nicholson, Jeremy K ^a  

^a IMPERIAL COLLEGE LONDON   (United Kingdom)

Author keywords

Deconjugation; Drug metabolism; Drugs; Gut bacteria; Metabolism; Microbiome; Prodrug activation; Toxicity; Xenobiotics

Indexed keywords

EID: 84978236925     PISSN: 21684219     EISSN: 21684235     Source Type: Book Series    
DOI: 10.1007/978-1-4471-6539-2_15     Document Type: Chapter

References (76)

1. Illing HPA. Techniques for microfloral and associated metabolic studies in relation to the absorption and enterohepatic circulation of drugs. Xenobiotica. 1981;11:815–30.
2. Boxenbaum HG, Bekersky I, Jack MJ, Kaplan SA. Influence of gut microflora on bioavailability. Drug Metab Rev. 1979;9:259–79.
3. Nicholson JK, Wilson ID. Understanding ‘global’ systems biology: metabonomics and the continuum of metabolism. Nat Rev Drug Discov. 2003;2:668–76.
4. Gingel R, Bridges JW. Intestinal azo-reduction and glucuronide conjugation of prontosil. Xenobiotica. 1973;9:599–604.
5. Gingel R, Bridges JW, Williams RT. The role of the gut flora in the metabolism of prontosil and neoprontosil in the rat. Xenobiotica. 1971;1:143–56.
6. Rafii F, Cerniglia CE. Reduction of azo dyes and nitroaromatic compounds by bacterial enzymes from the human intestinal tract. Environ Health Perspect. 1995;103 Suppl 5:17–9.
7. Peppercorn MA, Goldman P. The role of intestinal bacteria in the metabolism of salicylazosul-fapyridine. J Pharmacol Exp Ther. 1972;181:151–62.
8. Schroder H, Gustafsson BE. Azo reduction of salicyl-azosulphapyridine in germ free and conventional rats. Xenobiotica. 1973;3:225–31.
9. Truelove SC. Evolution of olsalazine. Scand J Gastroenterol. 1988;23(s148):3–6.
10. Chan RP, Pope DJ, Gilbert AP, Sacra PJ, Baron JH, Lennard-Jones JE. Studies of two novel sulfasalazine analogs, ipsalazide and balsalazide. Dig Dis Sci. 1983;28:609–15.
11. Takeno S, Sakai T. Involvement of the intestinal microflora in nitrazepam-induced teratogenic-ity in rats and its relationship to nitroreduction. Teratology. 1991;44:209–14.
12. Elmer GW, Remmel RP. Role of the intestinal microflora in clonazepam metabolism in the rat. Xenobiotica. 1984;14:829–40.
13. Antila S, Huuskonen H, Nevalainen T, Kanerva H, Vanninen P, Lehtonen L. Site dependent bioavailability and metabolism of levosimendan in dogs. Eur J Pharm Sci. 1999;9:85–91.
14. Antila S, Pesonen U, Lehtonen L, Tapanainen P, Nikkanen H, Vaahtera K, Scheinin H. Pharmacokinetics of levosimendan and its active metabolite OR-1896 in rapid and slow acetylators. Eur J Pharm Sci. 2004;23:213–22.
15. Deng Y, Rogers M, Sychterz C, Talley K, Qian Y, Bershas D, Ho M, Chen EP, Shi W, Chen EP, Serabjit-Singh C, Goryckj PD. Investigations of hydrazine cleavage of eltrombopag in humans. Investigations of hydrazine cleavage of eltrombopag in humans. Drug Metab Dispos. 2011;39:1747–54.
16. Strong HA, Renwick AG, George CF, Liu YF, Hill MJ. The reduction of sulphinpyrazone and sulindac by intestinal bacteria. Xenobiotica. 1987;17:685–96.
17. Watanabe K, Yamashita S, Furruno K, Kawasaki H, Gomita Y. Metabolism of omeprazole by gut flora in rats. J Pharm Sci. 1995;84:516–7.
18. Lindenbaum J, Tse-Eng D, Butler Jr VP, Rund DG. Urinary excretion of reduced metabolites of digoxin. Am J Med. 1981;71(1):67–74.
19. Dobkin JF, Saha JR, Butler Jr VP, Neu HC, Lindenbaum J. Inactivation of digoxin by Eubacterium lentum, an anaerobe of the human gut flora. Trans Assoc Am Physicians. 1982;95:22–9.
20. Saha JR, Butler Jr VP, Neu HC, Lindenbaum J. Digoxin-inactivating bacteria: identification in human gut flora. Science. 1983;220:325–7.
21. Bennet RG, Beamer BA, Greenough WB, Lindenbaum J, Bartlett JG. Colonisation with digoxin reducing strains of Eubacterium lentum and Clostridium difficile infection in nursing home patients. J Diarrhoeal Dis Res. 1992;10:87–92.
22. Linday L, Dobkin JF, Wang TC, Butler Jr VP, Saha JR, Lindenbaum J. Digoxin inactivation by the gut flora in infancy and childhood. Pediatrics. 1987;79:544–8.
23. Mathan VI, Wiederman J, Dobkin JF, Lindeenbaum J. Geographic differences in digoxin inactivation, a metabolic activity of the human anaerobic gut flora. Gut. 1989;30:971–7.
24. Haiser HJ, Gootenberg DB, Chatman K, Sirasani G, Balskus EP, Turnbaugh PJ. Predicting and manipulating cardiac drug inactivation by the human gut bacterium Eggerthella lenta. Science. 2013;341:295–8.
25. Koch RL, Chrystal EJT, Beaulieu Jr BB, Goldman P. Acetamide a metabolite of metronidazole formed by the intestinal flora. Biochem Pharmacol. 1979;28:3611–5.
26. Koch RL, Beaulieu BB, Goldman P. Role of the intestinal flora in the metabolism of misoni-dazole. Biochem Pharmacol. 1980;29:3281–4.
27. Koch RL, Goldman P. The anaerobic metabolism of metronidazole forms n-(2-hydroxyethyl)-oxamic acid. J Pharmacol Exp Ther. 1979;208:406–10.
28. Kitamura S, Sugihara K, Kuwasako M, Tatsumi K. The role of mammalian intestinal bacteria in the reductive metabolism of zonisamide. J Pharm Pharmacol. 1997;49:253–6.
29. Stiff DD, Robicheau JT. Reductive metabolism of the anticonvulsant agent zonisamide, a 1,2-benzisoxazole derivative. Xenobiotica. 1992;22:1–11.
30. Lavrijsen K, Van Dyck D, Van Houdt J, Hendrickx J, Monbaliu J, Woestenborghs R, Meuldermans W, Heykants J. Reduction of the prodrug loperamide oxide to its active drug loperamide in the gut of rats, dogs, and humans. Drug Metab Dispos. 1995;23:354–62.
31. Basit AW, Lacey LF. Colonic metabolism of ranitidine; implications for its delivery and absorption. Int J Pharm. 2001;227:157–65.
32. Basit AW, Newton JM, Lacey LF. Susceptibility of the H2-receptor antagonists cimetidine, famotidine and nizatidine, to metabolism by the gastrointestinal microflora. Int J Pharm. 2002;237:23–33.
33. Yunis AA. Chloramphenicol toxicity: 25 years of research. Am J Med. 1989;87(3N):44N–8.
34. Holt R. The bacterial degradation of chloramphenicol. Lancet. 1967;289(7502):1259–1260.
35. Jimenez JJ, Arimura GK, Abou-Khalil WH, Isildar M, Junis AA. Chloramphenicol-induced bone marrow injury: potential role of bacterial metabolites of chloramphenicol. Blood. 1987;70:1180–5.
36. Caldwell J, Hawksworth GM. The demethylation of methamphetamine by intestinal microflora. J Pharm Pharmacol. 1973;25:422–4.
37. Smith GE, Griffiths LA. Metabolism of N-acylated and O-alkylated drugs by the intestinal microflora during anaerobic incubation in vitro. Xenobiotica. 1974;4:477–87.
38. Sweeny DJ, Li W, Clough J, Bhamidipati S, Singh R, Park G, Baluom M, Elliott G, Lau DT-W. Metabolism of fostamatinib, the oral methylene phosphate prodrug of the spleen tyrosine kinase inhibitor R406 in humans: contribution of hepatic and gut bacterial processes to the overall biotransformation. Drug Metab Dispos. 2010;38:1166–76.
39. Calne DB, Karoum F, Ruthven CRJ, Sandler M. The metabolism of orally administered L-DOPA in Parkinsonism. Br J Pharmacol. 1969;37:57–68.
40. Sandler M, Goodwin BL, Ruthven CRJ, Calne DB. Therapeutic implications in Parkinsonism of m-tyramine formation from L-Dopa in man. Nature. 1971;229:414–6.
41. Bakke OM. Degradation of DOPA by intestinal microorganisms in vitro. Acta Pharmacol Toxicol. 1971;30:115–21.
42. Goldin BR, Peppercorn MA, Goldman P. Contribution of host and intestinal microflora in the metabolism of L-Dopa by the rat. J Pharmacol Exp Ther. 1973;186:160–6.
43. Peppercorn MA, Goldman P. Drug-bacteria interaction. Rev Drug Metab Drug Interact. 1976;11:75–88.
44. Sasahara K, Nitanai T, Habara T, Kojima T, Kawahara Y, Morioka T, Nakajima E. Dosage form design for improvement of bioavailability of levodopa IV: possible causes of low bioavailability of oral levodopa in dogs. J Pharm Sci. 1981;70:730–73.
45. Cole CB, Fuller R, Mallet AK, Rowland IR. The influence of the host on expression of intestinal microbial enzyme activities involved in metabolism of foreign compounds. J Appl Bacteriol. 1985;59:549–53.
46. Akao T, Kawabata K, Yanagisawa E, Ishiahara K, Mizuhara Y, Wakuia Y, Sakashita Y, Koashi K. Baicalin, the predominant flavone glucuronide of scutellariae radix, is absorbed from the rat gastrointestinal tract as the aglycone and restored to its original form. J Pharm Pharmacol. 2000;52:1563–8.
47. Bowey E, Adlercreutz H, Rowland I. Metabolism of isoflavones and lignans by the gut microflora: a study in germ-free and human flora associated rats. Food Chem Toxicol. 2003;41:631–6.
48. Turner NJ, Thomson BM, Shaw IC. Bioactive isoflavones in functional foods: the importance of gut microflora and bioavailability. Nutr Rev. 2003;61:204–13.
49. Wallace BD, Wang H, Lane KT, Scott JE, Orans J, Koo JS, Venkatesh M, Jobin C, Yeh L-AL, Mani S, Redinbo MR. Alleviating cancer drug toxicity by inhibiting a bacterial enzyme. Science. 2010;330:831–5.
50. LoGuidice A, Wallace BD, Bendel L, Redinbo MR, Boelsterli UA. Pharmacologic targeting of bacteria-glucuronidase alleviates nonsteroidal anti-inflammatory drug-induced enteropathy in mice. J Pharmacol Exp Ther. 2012;341:447–54.
51. Saitta KS, Carmen Z, Lee KK, Fujimoto K, Redinbo MR, Boelsterli UA. Bacterial β-glucuronidase inhibition protects mice against enteropathy induced by indomethacin, keto-profen or diclofenac: mode of action and pharmacokinetics. Xenobiotica. 2014;44:28–35.
52. Nakayama H, Kinouchi T, Kataoka K, Akimoto S, Matsuda Y, Ohnishi Y. Intestinal anaerobic bacteria hydrolyse sorivudine, producing the high blood concentration of 5-( E)-(2-bromovinyl) uracil that increases the level and toxicity of 5-fluorouracil. Pharmacogenetics. 1997;7:35–43.
53. Okuda H, Ogura K, Kato A, Takubo H, Watabe T. A possible mechanism of eighteen patient deaths caused by interactions of sorivudine, a new antiviral drug, with oral 5-fluorouracil pro-drugs. J Pharmacol Exp Ther. 1998;287:791–9.
54. Grant DM, Josephy PD, Lord HL, Morrison LD. Salmonella typhimurium strains expressing human arylamine N-acetyltransferases: metabolism and mutagenic activation of aromatic amines. Cancer Res. 1992;52:3961–4.
55. Hein DW, Doll MA, Rustan TD, Gray K, Feng Y, Ferguson RJ, Grant DM. Metabolic activation and deactivation of arylamine carcinogens by recombinant human NAT1 and NAT2 acetyltransferases. Carcinogenesis (Land). 1993;14:1633–8.
56. van Hogezand RA, Kennis HM, van Schaik A, Koopman JP, van Hees PA, van Tongeren JH. Bacterial acetylation of 5-aminosalicylic acid in faecal suspensions cultured under aerobic and anaerobic conditions. Eur J Clin Pharmacol. 1992;43:189–92.
57. Delome’nie C, Fouix S, Longuemaux S, Brahimi N, Bizet C, Picard B, Denamur F, Dupreet J-M. Identification and functional characterization of arylamine N-acetyltransferases in eubacteria: evidence for highly selective acetylation of 5-aminosalicylic acid. J Bacteriol. 2001;183:3417–27.
58. Garau P, Orenstein SR, Neigut DA, Kocoshis SA. Pancreatitis associated with olsalazine and sulfasalazine in children with ulcerative colitis. J Pediatr Gastroenterol Nutr. 1994;18:481–5.
59. Bakke JE, Gustafsson JA. Role of intestinal flora in metabolism of agrochemicals conjugated with glutathione. Xenobiotica. 1986;16:1047–56.
60. Mikov M, Caldwell J, Dolphin CT, Smith RL. The role of intestinal microflora in the formation of the methylthio adduct metabolites of paracetamol. Studies in neomycin-pretreated and germ-free mice. Biochem Pharmacol. 1988;37:1445–9.
61. Shu YZ, Kingston DGI, Van Tassall RL, Wilkins TD. Metabolism of levamisole, an anti-colon cancer drug by human intestinal bacteria. Xenobiotica. 1992;21:737–50.
62. Meuldermans W, Hendrickx J, Mannens G, Lavrijsen K, Janssen C, Bracke J, Le Jeune L, Lauwers W, Heykants J. The metabolism and excretion of risperidone after oral administration to rats and dogs. Drug Metab Dispos. 1994;22:129–38.
63. Rowland IR, Mallet AK, Cole CB, Fuller R. Mutagen activation by hepatic fractions from conventional, germ free and monoassociated rats. Arch Toxicol. 1987;11(Suppl):261–3.
64. Hooper LV, Wong MH, Thelin A, Hansson L, Falk PG, Gordon JI. Molecular analysis of commensal host-microbial relationships in the intestine. Science. 2001;291:881–3.
65. Meinl W, Sczesny S, Brigelius-Flohé R, Blaut M, Glatt H. Impact of gut microbiota on intestinal and hepatic levels of phase 2 xenobiotic-metabolizing enzymes in the rat. Drug Metab Dispos. 2009;37:1179–86.
66. Lhoste EF, Ouriet V, Bruel S, Flinois J-P, Brezillon C, Magdalou J, Cheze C, Nugon-Baudon L. The human colonic microbiota influences the alterations of xenobiotic-metabolizing enzymes by catechins in male F344 rats. Food Chem Toxicol. 2003;41:695–703.
67. Xu X, Duncan AM, Wangen KE, Kurzer MS. Soy consumption alters endogenous estrogen metabolism in postmenopausal women. Cancer Epidemiol Biomark Prev. 2000;9:781–6.
68. Clayton TA, Baker D, Lindon JC, Everett JR, Nicholson JK. Pharmacometabonomic identification of a significant host-microbiome metabolic interaction affecting human drug metabolism. Proc Natl Acad Sci U S A. 2009;106:14728–33.
69. Lee SH, An JH, Lee HJ, Jung BH. Evaluation of pharmacokinetic differences of acetaminophen in pseudo germ-free rats. Biopharm Drug Dispos. 2012;33:292–303.
70. Swann J, Wang Y, Abecia L, Costabile A, Tuohy K, Gibson G, Roberts D, Sidaway J, Jones H, Wilson ID, Nicholson J, Holmes E. Gut microbiome modulates the toxicity of hydrazine: a metabonomic study. Mol Biosyst. 2009;5:351–5.
71. Kang MJ, Kim HG, Kim JS, Oh DG, Um YJ, Seo CS, Han JW, Cho HJ, Kim GH, Jeong TC, Jeong HG. The effect of gut microbiota on drug metabolism. Expert Opin Drug Metab Toxicol. 2013;0:1–14.
72. Haiser HJ, Turnbaugh PJ. Is it time for a metagenomic basis of therapeutics? Science. 2012;336:1253–5.
73. Ursell LK, Knight R. Xenobiotics and the human gut microbiome: metatranscriptomics reveal the active players. Cell Metab. 2013;17:317–8.
74. Li H, Jia W. Cometabolism of microbes and host: implications for drug metabolism and drug-induced toxicity. Clin Pharmacol Ther. 2013;94:574–81.
75. Saad R, Rizkallah MR, Aziz RK. Gut Pharmacomicrobiomics: the tip of an iceberg of complex interactions between drugs and gut-associated microbes. Gut Pathog. 2012;4:16.
76. Jeong HG, Kang MJ, Kim HG, Oh DG, Kim JS, Lee SK, Jeong TC. Role of intestinal microflora in xenobiotic‐induced toxicity. Mol Nutr Food Res. 2013;57:84–99.